IE911067A1

IE911067A1 - Benzoxazine derivatives, process for their preparation and¹their use for the treatment or for the prophylaxis of¹diseases

Info

Publication number: IE911067A1
Application number: IE106791A
Authority: IE
Original assignee: Hoechst Ag
Priority date: 1990-03-31
Filing date: 1991-03-28
Publication date: 1991-10-09
Also published as: EP0450487A1; HU911053D0; NO911252L; NO911252D0; KR910016719A; FI911533L; AU7387491A; CA2039319A1; FI911533A0; PT97195A; ZA912363B; DE4010488A1; JPH04221380A; FI911533A7; IL97734A0; CS84891A2

Abstract

Benzoxazine derivatives of the formula I where R(1) and R(2) equal H, OH, alkoxy, Hal or a multiplicity of other substituents, R(3) equals alkyl or alkanoyl; R(4) equals H, alkyl or alkanoyl, and R(5) equals pyrid(azin)yloxy, pyrimidinyloxy, pyridazinyloxy and other heterocycles and their salts are useful medicaments for the treatment of disorders of the cardiovascular system, asthma, smooth muscle disorders, high blood pressure, cardiac arrhythmias and circulatory disorders of the brain; they are also used for topical application to control hair loss.

Description

Description Benzoxazine derivatives, process for their preparation and their use for the treatment or for the prophylaxis of diseases The invention relates to compounds I R ( 1 ) in which: R(l) and R(2), which are the same or different, are: a) hydrogen, (Cx-C4)-alkyl, OH, (Cx-C4)-Alkoxy, Cl, Br or b) one of the two substituents R(l) and R(2) has the meaning indicated under a) and the other is CHO, (Cx-C4)-alkylcarbonyl, (Cx-C4)alkyl-CS, (Cx-C4) -alkyl-OOC, (Cx-CJ -alkoxy-CS, (Cx-CJ -alkylene-COO, (Cx-CJ -alkylene-CS-O, hydroxy(Cx-CJ-alkyl, HS-(Cx-C4)-alkyl-, NO2, NH2, (Cx-CJalkylene-NH, di-(Cx-C4)-alkylamino, CN, Cl, Br, I, CF3, (Cx-CJ -alkyl-SO, (Cx-C4)-alkyl-SO2, (Cx-CJalkoxy-SO, (Cx«-C4) -alkoxy-S02, (Cx-C4)-alkanoyl-NH, benzamido, (Cj-C4)-alkoxy-CO-NH, H2NSO, (Cx-C4) -alkylNHSO, H2NSO2, (Cx-C4)-alkyl-NHSO2, di-(Cx-C4)-alkyl NSO2, H2NCO, (Cx-C4)-alkyl-NHCO, di-(Cx-C4)-alkyl-NCO, H2NCS, (Cx-C4)-alkyl-NHCS, di-(Cx-C4) -alkyl-NCS, (Cx-C4)-alkyl-SONH, (Cx-C4)-alkyl-SO2NH, (Cx-C4)alkoxy-SONH, (Ci-C4)-alkoxy-S02NH, nitro-(Cx-C4)alkyl, cyano-(Cx-C4)-alkyl or c) R(1) and R(2) are Ar-, ArO, ArCO, ArCS, ArSO, ArSO2, ArOSO, ArOSO2, ArNHSO, ArNHSO2, ArNHCO, ArNHCS, ArSONH, ArSOzNH, ArOSONH, ArSO2NH, - 2 in which Ar is an aromatic or heteroaromatic system which is unsubstituted or is substituted by 1 to 3 identical or different radicals (Ci-C2)-alkyl, (Cx-C2)-alkoxy, F, Cl, Br, I, CF3, CN, NO2, CO(Cj-Cj)-alkyl or SOp(C1-C2)-alkyl where p is one or two; R(3) is (Cx-CJ-alkyl, (Cj-CJ-alkanoyl; R(4) is hydrogen, (Cx-C^)-alkyl, (Cx-C4)-alkanoyl; R(3) and R(4) together are also (C3-C6)-alkylene; R(5) is unsubstituted or mono- or disubstituted by (Cj-CJ-alkyl, (Cx-C4)-alkylene, (Cx-CJ-alkanoyl, F, Cl, Br, I, OH, O(Cx-C4)-alkyl, O(Cx-C4) -alkylene, O(Cx-CJ-alkanoyl, N02, NH2, (Cx-CJ-alkanoyl-NH, HOOC or (Cx-C4)-alkyl-OOC, substituted pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, oxodihydropyridyloxy, oxodihydropyridazinyloxy, oxodihydropyrimidinyloxy, oxodihydropyrazinyloxy, ΙΗ-2-pyridon-l-yl, ΙΗ-6-pyridazinon-l-yl, ΙΗ-2-pyrimidinon-l-yl, ΙΗ-6-pyrimidinon20 1-yl, ΙΗ-2-pyrazinon-l-yl, ΙΗ-2-thiopyridon-l-yl, where the radicals can also be completely or partially hydrogenated, R(5) is additionally a ring I X in which X is a chain (CH2)a with m equal to two to 25 four, which is unsubstituted or substituted by 1 - 3 (Cx-C2)-alkyl groups, and which (CH2)m chain can be interrupted by a heteroatom Y with the meaning S, O or NR(6), where R(6) is hydrogen or (Cx-C4)-alkyl. and their pharmaceutically acceptable salts.

Preferred compounds I are those with R(l) and R(2) equal to hydrogen, methyl, ethyl, methoxy, ethoxy, acetyl, propionyl, thioacetyl, thiopropionyl, methoxycarbonyl, ethoxycarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, acetoxy, propionoxy, thioacetoxy, thiopropionoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy5 ethyl, mercaptomethyl, 1-mereaptoethyl, 2-mercaptoethyl, methylamino, ethylamino, dimethylamino, diethylamino, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, methoxysulfinyl, ethoxysulfinyl, methoxysulfonyl, ethoxysulfonyl, acetamido, formamido, propion10 amido, benzamido, methoxycarbonylamino, ethoxycarbonylamino, methylaminosulfinyl, ethylaminosulfinyl, methylaminosulfonyl, ethylaminosulfonyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methylthiocarbamoyl, N-ethylthiocarbamoyl, Ν,Ν-dimethylthiocarbamoyl, Ν,Ν-diethylthiocarbamoyl, methulsulfinylamino, ethylsulfinylamino, methylsulfonylamino, ethylsulfonylamino, methoxysulfonylamino, ethoxysulfonylamino, nitromethyl, 2-nitroethyl, cyanomethyl, 1- cyanoethyl, 2-cyanoethyl; phenyl, 4- or 2-chlorophenyl, o- or p-tolyl, phenoxy, 4- or 2-chlorophenoxy, o- or p-tolyloxy, benzoyl, 4- or 2-chlorobenzoyl, o- or ptoluoyl, benzylsulfinyl, 4- or 2-chlorobenzosulfinyl, o— or p-tolylsulfinyl, benzosulfonyl, 4- or 2-chlorobenzosulfonyl, o- or p-tolylsulfonyl, benzoxysulfinyl, 4- or 2-chlorobenzoxysulfinyl, o- or p-tolyloxysulfinyl, benzaminosulfinyl, 4- or 2-chlorobenzaminosulfinyl, o- or p-tolylaminosulfinyl, benzaminosulfonyl, 4- or 2-chlorobenzaminosulfonyl, o- or p-tolylaminosulfonyl, N-phenylcarbamoyl, N-[4- or 2-]chlorophenylcarbamoyl, o- or p-tolylcarbamoyl, N-phenylthiocarbamoyl, N-[4- or 2-]chlorophenylthiocarbamoyl, o- or p-tolylthiocarbamoyl, phenylsulfinylamino, 4- or 2-chlorophenylsulfinylamino, o— or p-tolylsulfinylamino, phenylsulfonylamino, 4- or 2- chlorophenylsulfonylamino, o- or p-tolylsulfonylamino, phenoxysulfinylamino, 4- or 2-chlorophenoxysulfinylamino, o— or p-tolyloxysulfinylamino, phenoxysulfonylamino, 4or 2-chlorophenoxysulfonylamino, o- or p-tolyloxysulfonylamino; R(3) is (Cx-C4)-alkyl; R(4) is hydrogen or (Cx-C4)-alkyl; and R(5) is as defined above.

Particularly preferred compounds I are those in which: R(l) is hydrogen, Cl, Br, N02, CN, (Cx-C4)-alkoxycarbonyl, (Cx-C4)-alkyl thio or phenylsulfonyl; R(2) is equal to hydrogen; R(3) and R(4) are (Cx-C4)-alkyl; R(5) is ΙΗ-2-pyridon-l-yl, 2-oxopyrrolidin-l-yl or 2-oxopiperidin-l-yl, which are unsubstituted or substituted by (Cx-C4)-alkyl.

Particularly preferred compounds I are those with: R(l) equal to N02, CN or phenylsulfonyl, R(2) equal to hydrogen, R(3) and R(4) equal to (Cx-C2)-alkyl and R(5) equal to 2-oxopyrrolidinyl.

The introduction of one or more substituents into the 2-oxopyrrolidinyl ring produces one or more asymmetric centers. The compounds according to the invention can then occur not only as antipodes, but in the case of several substituents also as diastereomers.

The invention was based on the object of finding novel compounds having valuable properties, which can be used as pharmaceuticals.

Surprisingly, a group of novel 1,3-benzoxazine derivatives of the formula I having valuable pharmacological properties was found. These compounds show a very good relaxing effect on the smooth musculature. They can therefore be employed both as bronchodilators in the treatment of respiratory disorders, in particular in bronchial asthma, and for the treatment of high blood pressure. They are additionally suitable for the treatment of contraction disorders of the smooth musculature of the gastrointestinal tract, of the uterus and of the urinary duct, including the ureter. The disturbances include premature labour, incontinence of the urinary bladder, renal colic, and the passage of kidney stones. The compounds can additionally be used in cardiovascular disorders which are not connected with the blood pressure, such as for the treatment and/or prophylaxis of pulmonary high blood pressure; moreoever in circulatory disorders of the brain, and for the treatment of hair loss (topical application), and they can show, for example, an antiarrhythmic or cardioprotective effect.

The invention also relates to a process for the preparation of the compound I, according to which compounds of the formula II in which the radicals R(l) to R(4) have the abovementioned meaning and whose preparation has been described in part in J. Med. Chem. 1987, 30, 205-208 and in Heterocycles Vol. 16, 1165 (1981), a) are reacted with R(5)H (III), in which R(5) has the meaning given in the formula I, or with one of its reactive derivatives.

Preferably, the compounds of the formula I are prepared by reaction of compounds of the formula II with compounds of the formula III in an inert solvent at 0 - 150’C.

It is advantageous to work in the presence of a base. Suitable bases are alkali metal or alkaline earth metal hydroxides, hydrides or, alternatively - 6 amides, such as NaOH, KOH, Ca(OH)2, NaH, NaNH2, and in addition organic bases such as triethylamine or pyridine.

Suitable inert solvents are ethers such as diethyl 5 ether, dioxane or tetrahydrofuran, amides such as dimethylformamide, and sulfoxides such as dimethyl sulfoxide. The reaction products can be separated and isolated without difficulty, for example by crystallization and/or chromatography.

The radical R(l) of the formula I can furthermore be converted into another radical.

For example, it is possible to replace a hydrogen atom [R(1)=H] by a nitro group by means of nitration and/or to reduce a nitro group to an amino group or to introduce a cyano group by reacting a halogen derivative of the formula I, for example R(l) or R(2) = Br, with CuCN.

Nitration is carried out under the customary conditions, for example with a mixture of concentrated HNO3 and concentrated H2SO4 in glacial acetic acid at temperatures from 0 to 30*C.

The introduction of a cyano group is carried out by reaction of the corresponding 6-Br-benzoxazine compounds with Cu(I) cyanide in dimethylformamide at temperatures of 120-160°C? b) or the compounds of the formula II are reacted with compounds of the formula IV H2N-(CH2)n+2C-L (IV) to give compounds of the formula V in which R(l) - R(4) are as defined above and L has the meaning of a leaving group, and these are cyclised to give compounds of the formula VI R(2) 'Oo R(1) U R (4 ) R ( 3 ) VI where n = 1 - 2.

The compounds of the formula I according to the invention are, as already mentioned, antihypertensives. They are additionally used in the therapy and/or prophylaxis of disorders of the cardiovascular system, in particular in decompensated cardiac insufficiency, angina pectoris and peripheral or cerebral vascular disorders. In addition, they can be used in disorders which are connected with changes in the non-vascular musculature, such as disorders of the respiratory passages, asthma or incontinence of the urinary bladder.

The compounds of the formula I can be employed in human and veterinary medicine. They are administered here enterally, for example orally or parenterally, for example intravenously, in dosages of at least 0.001 mg/kg/day, preferably 0.005 mg/kg/day and in particular 0.05 mg/kg/day up to a maximum of 10 mg/kg/day, - 8 preferably 5 mg/kg/day and in particular 2 mg/kg/day as capsules, coated tablets, tablets, powders, suppositories, solutions, spray or aerosol with additions or without additions of pharmaceutical auxiliaries, in each case relative to a weight of 75 kg. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.

EXAMPLES Preparation of the starting material: a) 219 g (1.6 mol) of salicylamide are stirred into a solution of 65 ml of dimethylformamide and 160 ml of 2,2-dimethoxypropane and the mixture is heated to reflux under nitrogen with 0.2 g of p-toluene sulfonic acid for 6 hours. After customary workingup, 3,4-dihydro-2,2-dimethyl-4-oxo-2H-l,3-benzoxazine is obtained. m.p. : 137°C (from methyl tert.-butyl ether). b) A solution of 53.1 g (0.3 mol) of the above 1,320 benzoxazine is stirred at 20 °C in a mixture of 62.3 g (0.3 mol) of phosphorus pentachloride and 28 ml of phosphorus oxychloride for one hour. After the vigorous evolution of HCI was over, the mixture was heated to 50 °C for a further 2 hours and the phosphorus oxychloride was then distilled off in a water-jet vacuum. After distillation in a high vacuum, 4-chloro-2,2-dimethyl-2H-l,3-benzoxazine of m.p. 85 - 90°C/0.05 mm Hg is obtained.

The following are obtained analogously: 6-Bromo-4-chloro-2,2-dimethyl-2H-l,3-benzoxazine, 4.6- Dichloro-2,2-dimethyl-2H-l,3-benzoxazine, 4-Chloro-2,2-diethyl-2H-l,3-benzoxazine, 4.6- Dichloro-2,2-diethyl-2H-l,3-benzoxazine.

,E 911067 Example 1 2.2- Diethyl-4- (2 ' -oxopyrrolidin-1' -yl) -2H-1,3-benzoxazine A solution of 6.8 g (0.08 mol) of pyrrolidin-2-one in 25 ml of DMSO was added slowly with stirring to a suspen5 sion of 2.4 g (0.08 mol) of sodium hydride (80% strength) in 50 ml of DMSO. 8.9 g (0.04 mol) of 4-chloro-2,2diethyl-1,3-benzoxazine were then added dropwise at 20°C. After standing overnight, the reaction product was heated to 50°C for a further 2 hours and, after cooling, added to ice-water. The precipitate was filtered off with suction, dried and recrystallized from petroleum ether. Crystals of m.p. 58°C.

Example 2 2.2- Diethyl-4-(3'-methyl-2'-oxopyrrolidin-1'-yl)-2H15 1,3-benzoxazine Analogously to Example 1 using 7.9 g (0.08 mol) of 3methylpyrrolidin-2-one. The final product was dissolved in hot petroleum ether and purified using active carbon. On cooling, the title compound precipitated in crystal20 line form.

Crystals of m.p. 69 - 70*C.

Example 3 2.2- Diethyl-4-(4'-methyl-2’-oxopyrrolidin-1'-yl)-2H1.3- benzoxazine Analogously to Example 1 using 7.9 g (0.08 mol) of 4methylpyrrolidin-2-one. The reaction product was extracted with methylene chloride after adding to ice-water; the organic phase was dried and evaporated and the residue was chromatographed on a silica gel column using dichloromethane/ethyl acetate/ethanol 94:3:3.

Crystals of m.p. 75 - 76eC (from petroleum ether) - ίο Example 4 6-Chloro-2,2-diethyl-4- (2 ' -oxopyrrolidin-1' -yl) -2H-1,3benzoxazine 1.6 ml (0.02 mol) of pyrrolidin-2-one were added dropwise 5 under nitrogen to a suspension of 0.6 g (0.02 mol) of sodium hydride (80% strength) in 10 ml of DMSO. After stirring at 20°C for 30 minutes, 5.2 g (0.02 mol) of 4,6dichloro-2,2-diethyl-2H-l,3-benzoxazine were added dropwise. The mixture was allowed to stand overnight and was then added to ice-water and extracted several times with methylene chloride. The combined organic phases were dried and evaporated, and the residue was chromatographed on a silica gel column using petroleum ether/ethyl acetate 3:1. The title compound was recrystallized from a little petroleum ether.

Crystals of m.p. 53°C.

Example 5 6-Chloro-2,2-diethyl-4-(3'-methyl-2'-oxopyrrolidin-1·yl)-2H-1,3-benzoxazine Analogously to Example 4 using 2 g (0.02 mol) of 3methylpyrrolidin-2-one. The yields were improved by allowing the sodium hydride suspension in DMSO to stand overnight with the 3-methylpyrrolidin-2-one and only then allowing 6.4 g (0.02 mol) of 4,6-dichloro-2,2-diethyl-2H25 1,3-benzoxazine to drip in under nitrogen. The mixture was subsequently stirred for 6 hours and added to icewater. On trituration with a glass rod, 6-chloro-2,2diethyl-4-(3'-methyl-2'-oxopyrrolidin-1'-yl)-2H-1,3benzoxazine crystallized. It was filtered off with suction, dried and dissolved in hot petroleum ether and the solution was purified with active carbon. On concentration, the title compound precipitated in crystalline form. - 11 Crystals of m.p. 67-68°C.

Example 6 2.2- Diethyl-6-nitro-4- (3 '-methyl-2' -oxopyrrolidin-1' -yl) 2H-1,3-benzoxazine ml (- 0.1 mol) of nitric acid (more than 90% strength) were added dropwise to a solution of 5.73 g (0.02 mol) of 2.2- diethyl-4-(3'-methyl-2'-oxopyrrolidin-1'-yl)-2H-1,3benzoxazine in 60 ml of glacial acetic acid. After addition of 20 ml of cone. H2SOA, the mixture was heated to 60°C for 5 minutes, then it was cooled to 20 °C, added to ice-water and extracted with dichloromethane. The combined organic phases were washed with water until neutral, concentrated and the residue was chromatographed on a silica gel column using petroleum ether/ethyl acetate 3:1.

Crystals of m.p. 91-92°C (from petroleum ether) Example 7 6-Ami no-2,2-diethyl-4- (3' -methyl-2' -oxopyrrolidin-1' -yl) 2H-1,3-benzoxazine A suspension of 0.3 g of Pd/C (10%) in 20 ml of water was added to a solution of 3.3 g (0.01 ml) of 2,2-diethyl-4( 3 '-methyl-2 '-oxopyrrolidin-1 '-yl)-6-nitro-2H-l,3-benzoxazine and the mixture was hydrogenated under normal conditions. After the calculated hydrogen absorption, the apparatus was flushed with nitrogen, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was recrystallized from diisopropyl ether.

Crystals of m.p. 69-72eC. - 12 Example 8 2.2- Dimethyl-4-(2 ' -oxopyrrolidin-1 '-yl) -2H-1,3-benzoxazine 11.4 ml (0.15 mol) of pyrrolidin-2-one were cautiously 5 added dropwise to a suspension of 4.5 g (0.15 mol) of sodium hydride (80% strength) in 45 ml of DMSO. The batch was allowed to stand overnight, then 19.6 g (0.1 mol) of 4-chloro-2,2-dimethyl-2H-l,3-benzoxazine were added dropwise with stirring. After stirring for six hours, the mixture was added to ice-water, the precipitate was washed with water until neutral and dissolved in dichloromethane, the solution was clarified with active carbon and concentrated, and the residue was recrystallized from diisopropyl ether.

Crystals of m.p. 125-126’C.

Example 9 2.2- Dimethyl-4- ( 3 ' -methyl-2 ' -oxopyrrolidin-1' -yl) -2H1.3- benzoxazine Analogously to Example 8 using 14.9 g (0.15 mol) of 3-methylpyrrolidin-2-one Crystals of m.p. 105°C.

Example 10 6-Chloro-2,2-dimethyl-4-(2'-oxopyrrolidin-1'-yl)-2H-1,3benzoxazine Analogously to Example 8 using 23 g (0.1 mol) of 4,6dichloro-2,2-dimethyl-2H-l,3-benzoxazine Crystals of m.p. 119C (from petroleum ether). - 13 Example 11 6-Bromo-2,2-dimethyl-4-(2 '-oxopyrrolidin-1 '-yl) -2H-1,3benzoxazine Analogously to Example 8 using 27.4 g (0.1 mol) of 65 bromo-4-chloro-2,2-dimethyl-2H-1,3-benzoxazine Crystals of m.p. 120’C (from diisopropyl ether).

Example 12 2,2-Dimethyl-6-nitro-4- (2 ' -oxopyrrolidin-1' -yl) -2H-1,3benzoxazine ml of fuming nitric acid were added dropwise at 20 °C to a solution of 3.2 g (0.013 mol) of 2,2-diethyl-4-(2'oxopyrrolidin-1'-yl)-2H-1,3-benzoxazine in 32 ml of cone, sulfuric acid and 32 ml of glacial acetic acid. After stirring for two hours, the mixture was added to ice15 water and extracted several times with 30 ml of dichloromethane each time. The combined organic phases were washed with water until approximately neutral, dried, concentrated and the residue was purified on a silica gel column using petroleum ether/ethyl acetate 3:1.

Crystals of m.p. 142-143°C (from diethyl ether) Example 13 6-Bromo-2,2-dimethyl-4-(3'-methyl-2'-oxopyrrolidin-1'yl)-2H-1,3-benzoxazine 9.9 g (0.1 mol) of 3-methylpyrrolidin-2-one were added under nitrogen to a suspension of 3 g (0.1 mol) of sodium hydride (80% strength) in 60 ml of DMSO and the mixture was allowed to stand at 20°C for several hours. 22 g (0.08 mol) of 6-bromo-4-chloro-2,2-dimethyl-2H-l,3benzoxazine were then added with stirring in small portions and the mixture was subsequently stirred for a further four hours. The reaction product was then added - 14 to ice-water and extracted several times with 50 ml of dichloromethane. The combined extracts were washed with water, dried and evaporated from impurities on a silica gel column using petroleum ether/ethyl acetate 3:1.

Crystals of m.p. 110-lll°C (from a little diisopropyl ether) Example 14 6-Cyano-2,2-dimethyl-4-(2 '-oxopyrrolidin-1 '-yl)-2H-l, 3benzoxazine 0.9 g (0.1 mol) of copper (I) cyanide was added to a solution of 2.6 g (0.08 mol) of 6-bromo-2,2-dimethyl-4(2'-oxopyrrolidin-l'-yl)-2H-l,3-benzoxazine in 25 ml of DMF and the mixture was heated to 150’C under nitrogen for 16 hours. After cooling to 20°C, the reaction product was stirred into ice-cold cone, ammonia solution and extracted with dichloromethane and diethyl ether. The combined organic phases were washed with water, dried and concentrated and the residue was chromatographed on a silica gel column using petroleum ether/ethyl acetate 1:1. The title compound crystallized from diisopropyl ether.

Crystals of m.p. 182-183’C.

Example 15 6-Cyano-2,2-dimethyl-4-(3'-methyl-2'-oxopyrrolidin-1'25 yl)-2H-l,3-benzoxazine Analogously to Example 14 using 6.7 g (0.02 mol) of 6bromo-2,2-dimethyl-4-(3'-methyl-2'-oxopyrrolidin-1'-yl)2H-1,3-benzoxazine and 1.8 g (0.02 mol) of copper(I) cyanide in 65 ml of DMF. After adding to the cold cone. ammonia solution, the mixture was extracted several times with dichloromethane. The combined organic phases were washed with water until neutral, dried, filtered and - 15 concentrated and the residue was recrystallized from hot diisopropyl ether.

Crystals of m.p. 116’C.

Claims

Patent Claims:

1. A compound I R ( 2) R(5> R(4 ) R< 3 > HOE 90/F 099 in which: R(l) and R(2), which are the same or different, are: a) hydrogen, (C x -C 4 )-alkyl, OH, (C x -C 4 )-Alkoxy, Cl, Br or b) one of the two substituents R(l) and R(2) has the meaning indicated under a) and the other is CHO, (C x -C 4 )-alkylcarbonyl, (C x -C 4 )alkyl-CS, (C x -C 4 ) -alkyl-OOC, (C x -C 4 )-alkoxy-CS, (C x —C 4 )—alkylene—COO, (C x -C 4 )-alkylene-CS-O, hydroxy(Ci-CJ-alkyl, HS-(C X -C 4 ) -alkyl-, NO 2 , NH 2 , (C x -C 4 )alkylene-NH, di-(C x -C 4 )-alkylamino, CN, Cl, Br, I, CF 3 , (C 1 -C 4 ) -alkyl-SO, (C x -C 4 ) -alkyl-SO 2 , (C x -C 4 )alkoxy-SO, (C x -C 4 )-alkoxy-S0 2 , (C x -C 4 )-alkanoyl-NH, benzamido, (C x -C 4 )-alkoxy-CO-NH, H 2 NSO, (C x -C 4 ) -alkylNHSO, H 2 NSO 2 , (C x -C 4 ) -alkyl-NHSO 2 , di-(C x -C 4 )-alkyl NS0 2 , H 2 NCO, (C x -C 4 )-alkyl-NHCO, di-(C x -C 4 )-alkyl-NCO, H Z NCS, (C x -C 4 )-alkyl-NHCS, di- (C x -C 4 ) -alkyl-NCS, (C x -C 4 ) -alkyl-SONH, (C x -C 4 ) -alkyl-SO 2 NH, (C x -C 4 )alkoxy-SONH, (C x -C 4 ) -alkoxy-SO z NH, nitro-(C x -C 4 )alkyl, cyano-(C x -C 4 )-alkyl or c) R(l) and R(2) are Ar-, ArO, ArCO, ArCS, ArSO, ArSO 2 , ArOSO, ArOSO 2 , ArNHSO, ArNHSO 2 , ArNHCO, ArNHCS, ArSONH, ArSO 2 NH, ArOSONH, ArSO 2 NH, in which Ar is an aromatic or heteroaromatic system which is unsubstituted or is substituted by 1 to 3 identical or different radicals - 17 (C x -C 2 )-alkyl, (C x -C 2 )-alkoxy, F, Cl, Br, I, CF 3 , CN, NO 2 , CO (C x -C 2 )-alkyl or SO p (C x -C 2 )-alkyl where p is one or two; R(3) is (C x -C 4 )-alkyl, (C x -C 4 )-alkanoyl; 5 R(4) is hydrogen, (C x -C 4 )-alkyl, (C x -C 4 )-alkanoyl; R(3) and R(4) together are also (C 3 -C 6 )-alkylene; R(5) is unsubstituted or mono- or disubstituted by (C x —C 4 )—alkyl, (C x -C 4 )-alkylene, (C x -C 4 )-alkanoyl, F, Cl, Br, I, OH, O(C X -C 4 )-alkyl, O(C X -C 4 )-alkylene, 10 O(C X -C 4 )-alkanoyl, NO 2 , NH 2 , (C x -C 4 )-alkanoyl-NH, HOOC or (C x -C 4 )-alkyl-OOC, substituted pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, oxodihydropyridyloxy, oxodihydropyridazinyloxy, oxodihydropyrimidinyloxy, oxodi15 hydropyrazinyloxy, ΙΗ-2-pyridon-l-yl, ΙΗ-6-pyridazinon-l-yl, ΙΗ-2-pyrimidinon-l-yl, ΙΗ-6-pyrimidinon1-yl, ΙΗ-2-pyrazinon-l-yl, ΙΗ-2-thiopyridon-l-yl, where the radicals can also be completely or partially hydrogenated, 20 R(5) is additionally a ring in which X is a chain (CH 2 ) m with m equal to two to four, which is unsubstituted or substituted by 1 - 3 (C x -C 2 )-alkyl groups, and which (CH 2 ) a chain can be interrupted by a heteroatom Y with the meaning S, 0 25 or NR(6), where R(6) is hydrogen or (C x -C 4 )-alkyl, and their pharmaceutically acceptable salts.

2. A compound I as claimed in claim 1, wherein R(1) and R(2) equal to hydrogen, methyl, ethyl, methoxy, ethoxy, acetyl, propionyl, thioacetyl, thiopropionyl, methoxycarbonyl, ethoxycarbonyl, methoxythiocarbonyl, -18ethoxythiocarbonyl, acetoxy, propionoxy, thioacetoxy, thiopropionoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl, methylamino, ethylamino, dimethylamino, diethylamino, 5 methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, methoxysulfinyl, ethoxysulfinyl, methoxysulfonyl, ethoxysulfonyl, acetamido, formamido, propionamido, benzamido, methoxycarbonylamino, ethoxycarbonylamino, methylaminosulfinyl, ethylaminosulfinyl, methyl10 aminosulfonyl, ethylaminosulfonyl, N-methylcarbamoyl, Nethylcarbamoyl, Ν,Ν-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methylthiocarbamoyl, N-ethylthiocarbamoyl, N,N-dimethylthiocarbamoyl, N,N-diethylthiocarbamoyl, methulsulfinylamino, ethylsulfinylamino, methylsulfonyl15 amino, ethylsulfonylamino, methoxysulfonylamino, ethoxysulfonylamino, nitromethyl, 2-nitroethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl; phenyl, 4- or 2-chlorophenyl, o— or p-tolyl, phenoxy, 4- or 2-chlorophenoxy, o- or p-tolyloxy, benzoyl, 4- or 2-chlorobenzoyl, o- or p20 toluoyl, benzylsulfinyl, 4- or 2-chlorobenzosulfinyl, oor p-tolylsulfinyl, benzosulfonyl, 4- or 2-chlorobenzosulfonyl, o- or p-tolylsulfonyl, benzoxysulfinyl, 4- or 2-chlorobenzoxysulfinyl, o- or p-tolyloxysulfinyl, benzaminosulfinyl, 4- or 2-chlorobenzaminosulfinyl, o- or 25 p-tolylaminosulfinyl, benzaminosulfonyl, 4- or 2-chlorobenzaminosulfonyl, o- or p-tolylaminosulfonyl, N-phenylcarbamoyl, N-[4- or 2-]chlorophenylcarbamoyl, o- or ptolylcarbamoyl, N-phenylthiocarbamoyl, N-[4- or 2-]chlorophenylthiocarbamoyl, o- or p-tolylthiocarbamoyl, 30 phenylsulfinylamino, 4- or 2-chlorophenylsulfinylamino, o— or p-tolylsulfinylamino, phenylsulfonylamino, 4- or 2chlorophenylsulfonylamino, o- or p-tolylsulfonylamino, phenoxysulfinylamino, 4- or 2-chlorophenoxysulfinylamino, o— or p-tolyloxysulfinylamino, phenoxysulfonylamino, 435 or 2-chlorophenoxysulfonylamino, o- or p-tolyloxysulfonylamino ; R(3) is (Cj-CJ-alkyl; R(4) is hydrogen or (Cx-C 4 )-alkyl; and R(5) is as defined as in claim 1.

3. A compound I as claimed in claim 1, wherein R( 1) is hydrogen, Cl, Br, NO 2 , CN, (Cx-C 4 )-alkoxycarbonyl, (Cx-C 4 )-alkylthio or phenylsulfonyl; R(2) is equal to hydrogen; R(3) and R(4) are (Ci~C 4 )-alkyl; R(5) is ΙΗ-2-pyridon-l-yl, 2-oxopyrrolidin-l-yl or 2-oxopiperidin-l-yl, which are unsubstituted or substituted by (Cx-C 4 )-alkyl.

4. A compound I as claimed in claim 1, wherein R(l) is equal to N0 2 , CN or phenylsulf onyl, R(2) is equal to hydrogen, R(3) and R(4) are equal to (Cx-C 2 )-alkyl and R(5) is equal to 2-oxopyrrolidinyl.

5. A process for the preparation of a compound I as claimed in claim 1, which comprises reacting a compound of the formula II in which the radicals R(l) to R(4) have the abovementioned meaning, a) with R(5)H (III) in which R(5) has the meaning given in the formula I, or with one of its reactive derivatives, or b) reacting the compound of the formula II with a compound of the formula IV H 2 N-(CH 2 ) n+2 C-L (IV) to give compounds of the formula V Rd ) fc(2) HN- ( CH 2 ) n +2 Cl- in which R(l) - R(4) are as defined in claim 1 and L has the meaning of a leaving group, and cyclising this to give a compound of the formula 10 VI where n = 1 - 2.

6. A compound I as claimed in claim 1 for use as a medicament for the therapy and prophylaxis of 15 disorders of the cardiovascular system.

7. A method for the treatment of disorders of the cardiovascular system by administration of a suitable amount of a compound I as claimed in claim 1.

8. The use of a compound as claimed in claim 1 as a - 21 medicament for the therapy of cardiac/circulatory disorders.

9. The use of a compound as claimed in claim 1 as a medicament against asthma.

10. The use of a compound as claimed medicament against smooth muscular in claim 1 as a disorders.

11. The use of a compound as claimed in claim 1 as a medicament for the control of high blood pressure.

12. The use of a compound as claimed in claim 1 as a medicament for cardioprotection and against cardiac arrhythmias.

13. The use of a compound as claimed in claim 1 as a medicament against circulatory disorders of the brain.

14. The topical application of a compound I as claimed in claim I for the control of hair loss. ΙΕ 9ΐ1θθ7

15. 15.

16. 16. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified . A compound as claimed in claim 1, whenever prepared by a process claimed in a preceding claim.